<p>In recent years, the role of novel protein acylation modifications in neuroinflammation has gradually become a hot research topic. In this paper, we reviewed the molecular mechanisms of five types of acylation modifications, namely lactylation (Kla), succinylation (Ksucc), crotonylation (Kcr), β-hydroxybutyrylation (Kbhb) and palmitoylation, and their association with neuroinflammation. To clarify the roles of these acylation modifications in neuroinflammation, we summarized the acyl donors, key regulatory enzymes (acyltransferases and deacylases), and dynamic regulatory networks for each modification type. On the one hand, they are directly involved in the inflammatory response by regulating microglial activation and pro-inflammatory factor release; on the other hand, they can indirectly affect the neurodegenerative disease process through metabolic reprogramming. This article also discusses drug development for novel acylases, including strategies based on enzyme activity inhibition or metabolic intervention, and points out the limitations of current studies. Future studies need to explore the spatial and temporal dynamics of acylation modifications, cross-regulatory networks and their functions in the neuroimmune microenvironment to provide new targets for the development of precise anti-neuroinflammatory therapies. The discovery of novel acylation modifications not only expands the theoretical framework of protein post-translational modification (PTM), but also opens up a multi-dimensional intervention pathway for the treatment of neuroinflammation-related diseases.</p>